Local anesthethic blockade of Ca 2+-mediated action potentials in cardiac muscle

Abstract

The effects of local anesthetic agents (lidocaine, procaine, cocaine) and diphenylhydantoin (DPH) were studied on the slow electrical responses induced by isoproterenol or caffeine in cardiac muscle preparations rendered inexcitabe by tetrodotoxin (TTX) or by partial depolarization with elevated K + (26 mM). In such inexcitable cells, we previously demonstrated that addition of some positive inotropic agents, such as catecholamines, histamine, and methylxanthines, rapidly increase the number of available slow Ca 2+Na + channels, thus allowing slowly rising electrical responses resembling the plateau component of the cardiac action potential. In embryonic chick (16–20-day-old) myocardial cells (ventricular) studied as intact perfused hearts or as reaggregated cell cultures of trypsin-dispersed cells, high concentrations (10 −3 M) of all the above drugs blocked the induced slow responses with their associated contractions; low concentrations (10 −5 M) of these agents reduce the maximal rate of rise (+V̇max) of the slow responses and depressed the contractions. For comparison with their effects on the slow response, the actions of these drugs on the normal action potential were also studied. As with the slow response, all of these drugs depressed the rate of rise of the action potential (10 −4 M) or blocked it at higher concentrations (10 −3 M); in contrast, low concentrations (10 −5 M) of lidocaine and DPH increased +V̇max. These findings suggest that local anesthetics, which interact with the lipid phase of the cell membrane, lead to blockade of the slow Ca 2+Na + channels as well as of the fast Na + channels in the myocardial sarcolemma.